A RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED TRIAL OF TIRILAZAD MESYLATE IN PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE - A COOPERATIVE STUDY IN NORTH-AMERICA

To test the safety and efficacy of tirilazad mesylate, a nonglucocorti coid 21-aminosteroid, in improving the outcome of patients with aneury smal subarachnoid hemorrhage (SAH), 902 patients were enrolled in a pr ospective randomized, double-blind, vehicle-controlled trial at 54 Nor th American neurosurgical centers. Five patients were excluded prior t o receiving any study drug. Of 897 patients who received at least one dose of study medication, 300 received a placebo containing a citrate vehicle, 298 received 2 mg/kg per day tirilazad, and 299 received 6 mg /kg per day tirilazad, all administered intravenously beginning within 48 hours of the SAH and continuing through 10 days posthemorrhage. Al l patients were also treated with orally administered nimodipine. At 3 months post-SAH, there were no significant differences (p < 0.025) am ong the groups with regard to mortality rate, favorable outcome on the Glasgow Outcome Scale, or employment status. During the first 14 days after the SAH, there were no significant differences among the groups in the incidence or severity of clinically symptomatic or angiographi cally identifiable cerebral vasospasm. Mortality data stratified by ge nder and neurological grade on admission (assessed according to a modi fied World Federation of Neurological Surgeons scale) demonstrated tha t the men with Grades lV to V had a 33% mortal ily rate in the vehicle group, 52% in the 2 mg/kg per day tirilazad group (D = 0.29), and 5% in the 6 mg/kg per day tirilazad group (p = 0.03). Tirilazad was well tolerated at both dose levels. Tirilazad mesylate at dosage levels of up to 6 mg/kg per day for 8 to 10 days following SAH did not improve t he overall outcome in patients with aneurysmal SAH in this trial. The differences in the efficacy of tirilazad in this trial and a previousl y reported trial in Europe, Australia, and New Zealand, in which dosag e levels of tirilazad of 6 mg/kg per day reduced mortality rates and i ncreased good recovery, may be a result of differences in admission ch aracteristics of the patients and/or differences in management protoco ls, including the use of anticonvulsant medications.